Inflammatory Cytokines at the Summits of Pathological Signal Cascades in Brain Diseases
ABSTRACT When considering the hierarchical organization of pathological signaling cascades in immunological disorders of the brain, certain cytokines might be considered pinnacles of pathophysiological importance, with their presence determining the appearance or the course of a particular disease. Interleukin-1 (IL-1), IL-6, IL-17, and tumor necrosis factor are critical for the pathogenesis of inflammation in specific brain disorders. Targeting these cytokines or their receptors can alter the course of several neurological diseases, but the effects may be beneficial or harmful.
- SourceAvailable from: Hideki Ogura
[Show abstract] [Hide abstract]
- "An increasing number of studies have shown that one cause of a dysfunctional BBB is inflammatory cytokines. For example, tumor-necrosis factor í µí»¼ (TNFí µí»¼), interleukin-(IL-) 1í µí»½, and IL-17A have all been reported to loosen the BBB . "
ABSTRACT: The central nervous system (CNS) is an immune-privileged environment protected by the blood-brain barrier (BBB), which consists of specific endothelial cells that are brought together by tight junctions and tight liner sheets formed by pericytes and astrocytic end-feet. Despite the BBB, various immune and tumor cells can infiltrate the CNS parenchyma, as seen in several autoimmune diseases like multiple sclerosis (MS), cancer metastasis, and virus infections. Aside from a mechanical disruption of the BBB like trauma, how and where these cells enter and accumulate in the CNS from the blood is a matter of debate. Recently, using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found a "gateway" at the fifth lumber cord where pathogenic autoreactive CD4+ T cells can cross the BBB. Interestingly, this gateway is regulated by regional neural stimulations that can be mechanistically explained by the gate theory. In this review, we also discuss this theory and its potential for treating human diseases.Mediators of Inflammation 08/2013; 2013:898165. DOI:10.1155/2013/898165 · 3.24 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The concept of the CNS as an immune-privileged organ has led to a common misunderstanding that it is not an active immunological organ, guarded from its surroundings by the blood-brain barrier (BBB). Recent advances in this field clearly demonstrate that the CNS is a highly immunologically active organ, with complex immune responses mostly based on innate immune processes. Such responses implicate a continuum of heterogeneous cell types both inside the CNS, in the periphery, and at their interface, the BBB. This Review aims to discuss the importance of the BBB as the first line of defense against brain infections and injuries of the CNS and the main molecular mechanisms involved in the control of the innate immune system of the CNS. We also review the central role of the neurovascular unit in diseases of the CNS and how it can be targeted for novel therapeutic strategies.Neuron 04/2013; 78(2):214-32. DOI:10.1016/j.neuron.2013.04.005 · 15.98 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The role of astrocytes in the immune-mediated inflammatory response in the brain is more prominent than previously thought. Astrocytes become reactive in response to neuro-inflammatory stimuli through multiple pathways, contributing significantly to the machinery that modifies the parenchymal environment. In particular, astrocytic signaling induces the establishment of critical relationships with infiltrating blood cells, such as lymphocytes, which is a fundamental process for an effective immune response. The interaction between astrocytes and T-cells involves complex modifications to both cell types, which undergo micro-anatomical changes and the redistribution of their binding and secretory domains. These modifications are critical for different immunological responses, such as for the effectiveness of the T-cell response, for the specific infiltration of these cells and their homing in the brain parenchyma, and for their correct apposition with antigen-presenting cells (APCs) to form immunological synapses (ISs). In this article, we review the current knowledge of the interactions between T-cells and astrocytes in the context of immune-mediated inflammation in the brain, based on the micro-anatomical imaging of these appositions by high-resolution confocal microscopy and three-dimensional rendering. The study of these dynamic interactions using detailed technical approaches contributes to understanding the function of astrocytes in inflammatory responses and paves the way for new therapeutic strategies.Frontiers in Cellular Neuroscience 04/2013; 7:58. DOI:10.3389/fncel.2013.00058 · 4.18 Impact Factor